Medical Pharmacology Chapter 36:  Antiviral Drugs

• Antiviral Drugs

  • Anti-viral drugs with activity against influenza.

    • Amantadine and Rimantadine

      • Drug Absorption and Elimination

        • Following oral administration, both amantadine and rimantadine are well absorbed.¹ 

          • Elderly patients require about one-half of the weight-adjusted amantadine dose required for young adults in order to obtain trough plasma levels of 0.3 µg/ml.

          • Both drugs exhibit very large volumes of distribution (V_d).

            • Volume of Distribution

              Volume of distribution (Vd) is the ratio between the amount of drug in body (dose given) and the concentration of the drug (C) measured in blood or plasma. Vd = (amount of drug in body)/C where C is the concentration of drug in blood or plasma. Vd as calculated is an apparent volume of distribution. For example: Vd for digoxin is 440 L/70 kg (liters per 70 kg person) Vd for chloroquine is 13,000 L/70 kg (liters per 70 kg person) Such very large Vd would be consistent with very high tissue binding, leaving little free in plasma or blood Vd is an apparent volume of distribution, since Vd is the volume needed to contain the amount of drug homogeneously at the concentration found in the blood, plasma, or plasma water. Many drugs have a much higher concentration in extravascular compartments (therefore these drugs are NOT homogeneously distributed). Factors influencing the volume of distribution: Drug pKa Extent of drug-plasma protein binding Partition coefficient of the drug in fat (lipid solubility) Vd may be affected by: Patient's gender Patient's age Patient's disease Patient's body composition Example of a poorly lipid soluble agent with a Vd about equal to extracellular fluid volume: nondepolarizing neuromuscular blocking drugs.

          • Amantadine is found in breast milk.

        • Amantadine is excreted by the kidney, mainly in an unmetabolized form following glomerular filtration and tubular secretion.¹

          • The plasma half-life elimination is about 12-18 hours in young adults.

          •   Given the dependence on renal function for drug elimination, in elderly patients and to a greater extent in those with renal impairment, elimination half-life may increase up to two fold.

            • Dose adjustments are appropriate in patients with mild renal impairment.¹

        • By contrast, rimantadine is metabolized mainly by hydroxylation, conjugation and glucuronidation before renal excretion occurs.

          • After oral dosing, the elimination half-life of rimantadine ranges from 24-36 hours with 60%-90% excreted in the urine as metabolites.¹

      • Adverse Effects:

        • Common adverse effects are both gastrointestinal and central nervous system-related.³ 

          • Gastrointestinal effects include:

            • Anorexia and

            • Nausea

          • CNS side effects include:

            • Insomnia

            • Nervousness

            • Lightheadedness and

            • Diminished concentration.

        • Side effects are dose-related and may decrease following continual drug treatment, even disappearing after one week of administration.³ 

        • The more serious CNS side effects including delirium, hallucinations, agitation and others may be related to amantadine effects on dopamine neurotransmission.

          • These effects appear less likely with rimantadine administration compared to amantadine.

        • CNS adverse effects may be more likely in patients with renal insufficiency, given amantadine clearance is mediated by the kidney, pre-existing seizure disorders or in elderly patients.

        • Administration of amantadine with other drugs including anticholinergic agents, hydrochlorothiazide (a diuretic), antihistamines, and trimethoprim-sulfamethoxazole may result in an increased incidence of adverse reactions.

        • Both amantadine and rimantadine are found teratogenic and embryotoxic in the rat model.³